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Purpose - Progression rate of age-related macular degeneration (AMD) varies substantially, yet its association with genetic variation has not been widely examined.
Methods - We tested whether progression rate from intermediate AMD to geographic atrophy (GA) or choroidal neovascularization (CNV) was correlated with genotype at seven single nucleotide polymorphisms (SNPs) in the four genes most strongly associated with risk of advanced AMD. Cox proportional hazards survival models examined the association between progression time and SNP genotype while adjusting for age and sex and accounting for variable follow-up time, right censored data, and repeated measures (left and right eyes).
Results - Progression rate varied with the number of risk alleles at the CFH:rs10737680 but not the CFH:rs1061170 (Y402H) SNP; individuals with two risk alleles progressed faster than those with one allele (hazard ratio [HR] = 1.61, 95% confidence interval [CI] = 1.08-2.40, P < 0.02, n = 547 eyes), although this was not significant after Bonferroni correction. This signal was likely driven by an association at the correlated protective variant, CFH:rs6677604, which tags the CFHR1-3 deletion; individuals with at least one protective allele progressed more slowly. Considering GA and CNV separately showed that the effect of CFH:rs10737680 was stronger for progression to CNV.
Conclusions - Results support previous findings that AMD progression rate is influenced by CFH, and suggest that variants within CFH may have different effects on risk versus progression. However, since CFH:rs10737680 was not significant after Bonferroni correction and explained only a relatively small portion of variation in progression rate beyond that explained by age, we suggest that additional factors contribute to progression.
The glomerular basement membrane (GBM) is an essential component of the glomerular filtration barrier. Heparan sulfate proteoglycans such as agrin are major components of the GBM, along with α345(IV) collagen, laminin-521 and nidogen. A loss of GBM heparan sulfate chains is associated with proteinuria in several glomerular diseases and may contribute to the underlying pathology. As the major determinants of the anionic charge of the GBM, heparan sulfate chains have been thought to impart charge selectivity to the glomerular filtration, a view challenged by the negligible albuminuria in mice that lack heparan sulfate in the GBM. Recent studies provide increasing evidence that heparan sulfate chains modulate local complement activation by recruiting complement regulatory protein factor H, the major inhibitor of the alternative pathway in plasma. Factor H selectively inactivates C3b bound to surfaces bearing host-specific polyanions such as heparan sulfate, thus limiting complement activation on self surfaces such as the GBM, which are not protected by cell-bound complement regulators. We discuss mechanisms whereby the acquired loss of GBM heparan sulfate can impair the local regulation of the alternative pathway, exacerbating complement activation and glomerular injury in immune-mediated kidney diseases such as membranous nephropathy and lupus nephritis.
Copyright © 2016 Elsevier B.V. All rights reserved.
Mutations in the complement regulatory proteins are associated with several different diseases. Although these mutations cause dysregulated alternative pathway activation throughout the body, the kidneys are the most common site of injury. The susceptibility of the kidney to alternative pathway-mediated injury may be due to limited expression of complement regulatory proteins on several tissue surfaces within the kidney. To examine the roles of the complement regulatory proteins factor H and Crry in protecting distinct renal surfaces from alternative pathway mediated injury, we generated mice with targeted deletions of the genes for both proteins. Surprisingly, mice with combined genetic deletions of factor H and Crry developed significantly milder renal injury than mice deficient in only factor H. Deficiency of both factor H and Crry was associated with C3 deposition at multiple locations within the kidney, but glomerular C3 deposition was lower than that in factor H alone deficient mice. Thus, factor H and Crry are critical for regulating complement activation at distinct anatomic sites within the kidney. However, widespread activation of the alternative pathway reduces injury by depleting the pool of C3 available at any 1 location.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
PURPOSE - To compare plasma levels of oxidative stress biomarkers in patients with age-related macular degeneration (AMD) and controls and to evaluate a potential relationship between biochemical markers of oxidative stress and AMD susceptibility genotypes.
DESIGN - Prospective case-control study.
METHODS - Plasma levels of oxidative stress biomarkers were determined in 77 AMD patients and 75 controls recruited from a clinical practice. Cysteine, cystine (CySS), glutathione, isoprostane, and isofuran were measured, and participants were genotyped for polymorphisms in the complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes.
RESULTS - CySS was elevated in cases compared with controls (P = .013). After adjustment for age, sex, and smoking, this association was not significant. In all participants, CySS levels were associated with the CFH polymorphism rs3753394 (P = .028) as well as an 8-allele CFH haplotype (P = .029) after correction for age, gender, and smoking. None of the other plasma markers was related to AMD status in our cohort.
CONCLUSIONS - Our investigation of the gene-environment interaction involved in AMD revealed a relationship between a plasma biomarker of oxidative stress, CySS, and CFH genotype. These data suggest a potential association between inflammatory regulators and redox status in AMD pathogenesis.
Copyright Â© 2012 Elsevier Inc. All rights reserved.
AIMS - To determine whether complement factor H (CFH) genotypes have a pharmacogenetic effect on the treatment of exudative age-related macular degeneration (AMD) with ranibizumab.
METHODS - A retrospective study of 156 patients with exudative AMD treated with intravitreal ranibizumab monotherapy was conducted. AMD phenotypes were characterised by clinical examination, visual acuity, fundus photography, fluorescein angiography and injection timing. Patients received intravitreal ranibizumab injections as part of routine ophthalmological care and were followed for a minimum of 9 months. Each patient was genotyped for the single nucleotide polymorphism rs1061170 (Y402H) in the CFH gene.
RESULTS - Baseline lesion size and angiographic type, as well as mean visual acuities at baseline, 6 months, and 9 months were similar among the three CFH genotypes. Over 9 months, patients with both risk alleles received approximately one more injection (p = 0.09). In a recurrent event analysis, patients homozygous for the CFH Y402H risk allele had a 37% significantly higher risk of requiring additional ranibizumab injections (p = 0.04).
CONCLUSIONS - In this study cohort, the response to treatment of AMD with ranibizumab differed according to CFH genotype, suggesting that determining patients' CFH genotype may be helpful in the future in tailoring treatment for exudative AMD with intravitreal ranibizumab.
AIM - To determine whether there is an association between complement factor H (CFH) or LOC387715 genotypes and response to treatment with photodynamic therapy (PDT) for exudative age-related macular degeneration (AMD).
METHODS - Sixty-nine patients being treated for neovascular AMD with PDT were genotyped for the CFH Y402H and LOC387715 A69S polymorphisms by allele-specific digestion of PCR products. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography.
RESULTS - Adjusting for age, pre-PDT visual acuity (VA), and lesion type, mean VA after PDT was significantly worse for the CFH TT genotype than for the TC or CC genotypes (P=0.05). Post-PDT VA was significantly worse for the CFH TT genotype in the subgroup of patients with predominantly classic choroidal neovascular lesions (P=0.04), but not for the patients with occult lesions (P=0.22). For the LOC387715 A69S variant, there was no significant difference among the genotypes in response to PDT therapy.
CONCLUSIONS - The CFH Y402H variant was associated with a response to PDT treatment in this study. Patients with the CFH TT genotype fared significantly worse with PDT than did those with the CFH TC and CC genotypes, suggesting a potential relationship between CFH genotype and response to PDT.
PURPOSE - To investigate whether there is an association between complement factor H (CFH) or LOC387715 genotypes with response to treatment with intravitreal bevacizumab for exudative age-related macular degeneration (AMD).
DESIGN - Retrospective cohort study.
PARTICIPANTS - The study cohort consisted of 86 patients being treated for neovascular AMD with bevacizumab alone.
METHODS - Genotype determination for the CFH Y402H and LOC387715 A69S polymorphisms was performed by allele-specific digestion of polymerase chain reaction products. All patients were treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization was no longer active.
MAIN OUTCOME MEASURES - CFH Y402H and LOC387715 A69S polymorphisms. Choroidal neovascular lesion characteristics were ascertained by fluorescein angiography. Snellen visual acuity (VA) was measured before and after treatment.
RESULTS - For the CFH Y402H polymorphism, patients with the CFH TT genotype had the largest choroidal neovascular lesions (P = 0.02). With treatment, VA improved from 20/248 to 20/166 for the CFH TT genotype and from 20/206 to 20/170 for the TC genotype, but fell from 20/206 to 20/341 for the CFH CC genotype (P = 0.016). Only 10.5% of patients with the CFH CC genotype demonstrated improved VA with treatment, compared with 53.7% of CFH TT and TC genotypes (P = 0.004). For the LOC387715 A69S variant, patients with the TT genotype had the largest choroidal neovascular lesions (P = 0.012). There was no significant difference in response to bevacizumab treatment according to LOC387715 genotype.
CONCLUSIONS - The AMD-associated CFH Y402H and LOC387715 A69S variants were associated with differences in choroidal neovascular lesion size in this study. Patients with the CFH CC genotype fared significantly worse with intravitreal bevacizumab than did those with the CFH TC and TT genotypes, suggesting a potential pharmacogenetic relationship. Prospective studies to confirm or refute this observation should be considered.
PURPOSE - To determine whether the complement factor H (CFH) Y402H variant is associated with specific age-related macular degeneration (AMD) clinical phenotypes.
DESIGN - Retrospective, case-control study.
METHODS - One hundred and eighty-eight white subjects with AMD and 189 control subjects were genotyped for the T-to-C polymorphism in exon 9 of the CFH gene by restriction-fragment length analysis and deoxyribonucleic acid (DNA) sequencing using genomic DNA from mouthwash samples. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography.
RESULTS - Heterozygosity for the at-risk genotype (TC) increased the likelihood for AMD 2.1-fold (95% confidence interval [CI], 1.3 to 3.3), whereas homozygosity for the genotype (CC) increased the likelihood for AMD 6.5-fold (95% CI, 3.4 to 12.5) in our population. The C allele was associated significantly with predominantly classic choroidal neovascularization (odds ratio [OR], 2.01; 95% CI, 1.34 to 3.30). Neovascular lesion size was similar among the three genotypes (P = .67).
CONCLUSIONS - The Y402H CFH variant carried a significantly increased risk for developing AMD in our population. Genotype and phenotype correlations regarding choroidal neovascular lesion type were observed.